This invention relates to the use of certain benzopyran and benzo-fused compounds and their pharmaceutically acceptable acid addition salts for the prevention of allograft rejection in mammals, including humans.
Allograft rejection, be it of a vascularized organ, skin or tissue, is characterized by a highly complex series of cellular and humoral interactions in which T lymphocytes play a central, essential role. T cells initiate and regulate graft rejection, but a mixed population of cells and effector mechanisms contribute to graft failure. This wide array of effector mechanisms leading to graft destruction include alloantibody dependent mechanisms (B lymphocytes) antigen-specific cytotoxic T cells and a variety of non- specific effector cells including macrophages, natural killer (NK) cells, polymorphonuclear leukocytes (PMN, e.g., neutrophils, eosinophils), and lymphokine- activated killer (LAK) cells. The cellular pathways which mediate graft rejection are multiple and complex.
Acute cellular rejection is the result of migration of inflammatory cells into the graft. Lymphocytes recognize and react to foreign antigens, undergo proliferative expansion and initiate humoral events, i.e., antibodies, cytokines, and proinflammatory mediators; these in turn recruitactivate, non-specifically, various cells of the monocyte/macrophage lineage to infiltrate and destroy graft tissue. Also, at this point, large granular lymphocytes and PMN may be seen in the graft.
Secondarily, most grafts are subject to ischemic injury due to cold ischemia time and vasoconstriction of donor arteries following reperfusion and high dose immunosuppression immediately after transplantation. This event is characterized by infiltration of the graft by inflammatory cells, primarily, monocytes, macrophages and PMN. The donor arterial endothelial cells are most likely the primary target of transplant ischemia-reperfusion injury. This lesion is characterized by a local, chronic cellular immune response of the endothelium composed of T cells and macrophages which continue to amplify and perpetuate the immune/inflammatory response, resulting in loss of intact endothelium and function combined with chronic immunologic injury.
The incidence of transplant associated arteriosclerosis escalates with increasing survival time; lesions develop rapidly (within 3 months) and occur throughout the arterial tree of the graft. Chronic rejection leads to gradual deterorationof graft function and is a major threat to long-term survival of transplanted organs.